Lesions containing abnormal aggregated tau protein are one of the diagnostic hallmarks of Alzheimer's disease (AD) and related tauopathy disorders. How aggregated tau leads to the dysfunction and loss of neurons in AD patients remains enigmatic, although neuronal dysfunction and/or loss clearly cause dementia. To better understand how abnormal tau contributes to neurodegeneration in AD and other tauopathies, we have established a model in C. elegans for tau aggregation and consequent neurodegeneration. Through the course of investigating the genes required for tau neurotoxicity, we have identified the suppressor of tauopathy 2 (sut-2) gene. We focused on sut-2 because it has a well conserved homologous gene in all animal species including humans. We call the human homolog of sut-2 mammalian SUT2 (MSUT2). Unfortunately very little is known about the normal function of MSUT2 and its role in tau pathology. However, our early findings suggest MSUT2 may participate in aggresome formation and show MSUT2 depletion in regions of the AD brain with heavy loads of tau pathology. The goals of this project are to determine whether or not MSUT2 is required for tau neurotoxicity in mammals as sut-2 is in worms; explore the mechanistic role MSUT2 might play in the formation and clearance of tau containing aggresomes; and identify other genes and pathways that interact with C. elegans sut-2. To address the functional role of MSUT2 in tau neurotoxicity, we propose to generate gene targeted Msut2 mice and study the effects of loss of Msut2 on an existing mouse model of tau pathology. To explore the role of MSUT2 and its binding partners in aggresome formation, we have generated a cell culture model for tau containing aggresomes and propose functional studies where we will knock down MSUT2 and related binding partners using gene specific RNAi. To identify genetic interactions with sut-2, we propose to conduct an RNAi screen in C. elegans looking for genes that specifically alter the sut-2 suppression of tauopathy phenotype. As an aging population, Veterans are susceptible to a variety of geriatric diseases including AD. If loss of Msut2 suppresses tauopathy in mice, then human MSUT2 is a strong candidate target for therapeutic intervention in diseases with tau pathology. The identification of new therapeutic strategies for AD will benefit not only Veterans, but all people susceptible to AD.